Protective groups and methods for protecting benzoxaboroles or oxaboroles

ABSTRACT

The present invention relates in part to protective groups that can be used to reversibly protect benzoxaboroles and/or oxaboroles and yield the corresponding protected complexes. The invention further relates to the use of these protective groups to protect benzoxaboroles and/or oxaboroles.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 62/640,916, filed Mar. 9, 2018, which ishereby incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

The incorporation of boronic acids and benzoxaboroles intopharmaceutical agents has led to increased interest in the interactionsof such compounds with biological targets, based on the Lewis acidicnature of boron. These interactions arise from an empty p-orbital on theboron atom, resulting in the unique ability to reversibly bond to Lewisbasic amino acids in enzyme active sites.

Benzoxaboroles in particular have become increasingly relevant in drugdesign and in the pharmaceutical industry. They are cyclic boronateester derivatives of phenyl boronic acid, which contain a phenyl ringfused to a 5-membered oxaborole ring (Scheme 1). These compounds haveenhanced reactivity resulting from ring strain about the boron center.Two benzoxaborole-containing drugs have recently been approved by theFDA: KERYDIN® (tavaborole), an aminoacyl-transfer ribonucleic acid(tRNA) synthetase inhibitor used for the treatment of onychomycosis(toenail fungus), and EUCRISA® (crisaborole), a PDE-4 enzyme inhibitorused for the treatment of atopic dermatitis (eczema). Benzoxaboroleshave also been shown to exhibit other types of bioactivity includingantibacterial, antiviral, and anti-malarial activity.

Benzoxaboroles are generally considered more stable than their boronicacid counterparts. However, the possibility of side reactivity arisingfrom a more reactive p-orbital about the boron center is of concern whenreacting with nucleophiles and oxidizing agents. Additionally, a lack oforganic solubility arises as substituents capable of hydrogen bonding,and/or polymerizing via condensation, are introduced on thebenzoxaborole scaffold. In the case of boronic acids, these issues areaddressed with a series of widely used protecting groups, such asN-methylimidodiacetic boronic acid esters (MIDA boronates) andtrifluoroborate salts.

There has been only one benzoxaborole protecting group validated in theliterature: 1-dimethylamino-8-methylaminonaphthalene. While stable to avariety of reaction conditions and column chromatography, thisprotecting group is not stable to oxidation, and its subsequent removalwith re-isolation of the benzoxaborole has not been described.

There is thus a need in the art for novel protective groups and methodsfor reversibly protecting benzoxaboroles and/or oxaboroles. The presentinvention fulfills this need.

BRIEF SUMMARY OF THE INVENTION

The invention provides a compound of formula (II) or (II′), or a salt,solvate, enantiomer, diastereoisomer or tautomer thereof:

wherein:

each occurrence of R¹ is independently selected from the groupconsisting of H, OH, halide, amine, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, C(═O)N((C₁-C₄)alkyl)₂, —C(═NH)NH₂,phosphoric acid, phosphonate, sulfonamide, nitro, cyano, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈ heteroalkyl, optionally substituted C₃-C₈heterocycloalkyl, optionally substituted C₁₋₆ perhaloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, and optionally substituted benzyl,

R² is selected from the group consisting of H, halo, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈ heteroalkyl, optionally substituted C₃-C₈heterocycloalkyl, and optionally substituted C₁₋₆ perhaloalkyl;

each occurrence of R³ is independently selected from the groupconsisting of H, OH, halide, amine, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₁-C₈ heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl,optionally substituted C₁₋₆ perhaloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,optionally substituted benzyl, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, and—C(═NH)NH₂;

each occurrence of R⁴ is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl,and optionally substituted C₃-C₈ heterocycloalkyl; and each occurrenceof R⁵ is independently selected from the group consisting of H andoptionally substituted C₁₋₆ alkyl, halide, nitro, and nitrile.

The invention further provides a compound of formula (I) or (I′), or asalt, solvate, enantiomer, diastereoisomer or tautomer thereof:

wherein:

each occurrence of R¹ is independently selected from the groupconsisting of H, halide, amine, sulfonamide, nitro, cyano, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₃-C₈ heterocycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted aryloxy, optionally substituted heteroaryl, andoptionally substituted heteroaryloxy;

each occurrence of R² is independently selected from the groupconsisting of H, halide, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl, andoptionally substituted C₁₋₆ perhaloalkyl;

each occurrence of R³ is independently selected from the group selectedfrom the group consisting of H and optionally substituted C₁-C₆ alkyl;

each occurrence of R⁴ is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl,and optionally substituted C₃-C₈ heterocycloalkyl.

The invention further provides a compound, or a salt, solvate,enantiomer, diastereoisomer or tautomer thereof, selected from the groupconsisting of:

In certain embodiments, each occurrence of R¹ is independently selectedfrom the group consisting of OMe, C₁₋₆ alkoxy, NO₂, CH₂OH, CH₂I, CHO,CN, F, Cl, Br, I, CF₃, CH₂Cl, CH₂Br, C₁₋₆ carboxylate, C₁₋₆ thioether

wherein each occurrence of R^(x) is independently selected from thegroup consisting of H and optionally substituted C₁₋₆ alkyl.

In certain embodiments, each occurrence of R¹ is independently selectedfrom the group consisting of H, NO₂, CH₂OH, CH₂I, CHO, CN, F,

In certain embodiments, each occurrence of R³ is independently selectedfrom the group consisting of H, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkyl cyano, optionally substituted C₁₋₆nitroalkyl, optionally substituted C₁₋₆ aminoalkyl,

In certain embodiments, the compound is a compound of formula (Ia) or(Ia′):

wherein:

each occurrence of R¹ is independently selected from the groupconsisting of H, halide, amine, sulfonamide, nitro, cyano, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₃-C₈ heterocycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted aryloxy, optionally substituted heteroaryl, andoptionally substituted heteroaryloxy;

each occurrence of R³ is independently selected from the groupconsisting of H and optionally substituted methyl;

each occurrence of R⁴ is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl,and optionally substituted C₃-C₈ heterocycloalkyl.

In certain embodiments, the compound is a compound of formula (IIa) or(IIa′):

wherein R² is selected from the group consisting of H and methyl.

In certain embodiments, the compound of formula (IIa) is a compoundselected from the group consisting of:

wherein R² is selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, and optionally substituted C₃-C₈ cycloalkyl.

The invention further provides a method of protecting a boronic acidgroup.

In certain embodiments, the method comprises reacting a boronic acidcontaining compound with a compound of formula (III) or formula (IV):

wherein each occurrence of R² is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, halide, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl, andoptionally substituted C₁₋₆ perhaloalkyl;

each occurrence of R⁴ is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl,and optionally substituted C₃-C₈ heterocycloalkyl; and

each occurrence of R⁵ is independently selected from the groupconsisting of H, halide, nitro, nitrile and optionally substituted C₁₋₆alkyl.

In certain embodiments, the boronic acid containing compound is a(benz)oxaborole.

In certain embodiments, the (benz)oxaborole is a compound of formula:

wherein:

each occurrence of R¹ is independently selected from the groupconsisting of H, OH, halide, amine, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —C(═NH)NH₂,phosphoric acid, phosphonate, sulfonamide, nitro, cyano, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈ heteroalkyl, optionally substituted C₃-C₈heterocycloalkyl, optionally substituted C₁₋₆ perhaloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, and optionally substituted benzyl; and

each occurrence of R³ is independently selected from the groupconsisting of H, OH, halide, amine, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₁-C₈ heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl,optionally substituted C₁₋₆ perhaloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,optionally substituted benzyl, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, and—C(═NH)NH₂;

In certain embodiments, the boronic acid containing compound is selectedfrom the group consisting of:

In certain embodiments, the method further comprises reacting theboronic acid containing compound with a compound of formula (IIIa) orformula (IVa):

The invention further provides a method of deprotecting a boronic acidcontaining compound.

In certain embodiments, the method comprises contacting a protected(benz)oxaborole compound of the invention with an acidic solution toyield a (benz)oxaborole of formula:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates in part to the unexpected discovery ofprotective groups that can be used to reversibly protect benzoxaborolesand yield the corresponding protected complexes. The invention furtherrelates to the use of these protective groups to protect benzoxaboroles.

Definitions

As used herein, each of the following terms has the meaning associatedwith it in this section.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in separationscience, organometallic chemistry, inorganic chemistry, and organicchemistry are those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e., to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.

As used herein, the term “about” is understood by persons of ordinaryskill in the art and varies to some extent on the context in which it isused. As used herein when referring to a measurable value such as anamount, a temporal duration, and the like, the term “about” is meant toencompass variations of ±20% or ±10%, more preferably ±5%, even morepreferably ±1%, and still more preferably ±0.1% from the specifiedvalue, as such variations are appropriate to perform the disclosedmethods.

As used herein, the term “alkenyl,” employed alone or in combinationwith other terms, means, unless otherwise stated, a stablemonounsaturated or di-unsaturated straight chain or branched chainhydrocarbon group having the stated number of carbon atoms. Examplesinclude vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl,1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. Afunctional group representing an alkene is exemplified by —CH₂—CH═CH₂.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms, as defined above, connected to therest of the molecule via an oxygen atom, such as, for example, methoxy,ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs andisomers. A specific example is (C₁-C₃)alkoxy, such as, but not limitedto, ethoxy and methoxy.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁-C₁₀means one to ten carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. A selected example is (C₁-C₆)alkyl, such as, but notlimited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl andcyclopropylmethyl.

As used herein, the term “alkynyl,” employed alone or in combinationwith other terms, means, unless otherwise stated, a stable straightchain or branched chain hydrocarbon group with a triple carbon-carbonbond, having the stated number of carbon atoms. Non-limiting examplesinclude ethynyl and propynyl, and the higher homologs and isomers. Theterm “propargylic” refers to a group exemplified by —CH₂—C≡CH. The term“homopropargylic” refers to a group exemplified by —CH₂CH₂—C≡CH. Theterm “substituted propargylic” refers to a group exemplified by—CR₂—C≡CR′, wherein each occurrence of R′ is independently H, alkyl,substituted alkyl, alkenyl or substituted alkenyl, with the proviso thatat least one R′ group is not hydrogen. The term “substitutedhomopropargylic” refers to a group exemplified by —CR′₂CR′₂—C≡CR′,wherein each occurrence of R′ is independently H, alkyl, substitutedalkyl, alkenyl or substituted alkenyl, with the proviso that at leastone R′ group is not hydrogen.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e. having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings)wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples includephenyl, anthracyl, and naphthyl.

As used herein, the term “aryl-(C₁-C₃)alkyl” refers to a functionalgroup wherein a one to three carbon alkylene chain is attached to anaryl group, e.g., —CH₂CH₂-phenyl or —CH₂-phenyl (benzyl). Specificexamples are aryl-CH₂— and aryl-CH(CH₃)—. The term “substitutedaryl-(C₁-C₃)alkyl” refers to an aryl-(C₁-C₃)alkyl functional group inwhich the aryl group is substituted. A specific example is substitutedaryl(CH₂)—. Similarly, the term “heteroaryl-(C₁-C₃)alkyl” refers to afunctional group wherein a one to three carbon alkylene chain isattached to a heteroaryl group, e.g., —CH₂CH₂-pyridyl. A specificexample is heteroaryl-(CH₂)—. The term “substitutedheteroaryl-(C₁-C₃)alkyl” refers to a heteroaryl-(C₁-C₃)alkyl functionalgroup in which the heteroaryl group is substituted. A specific exampleis substituted heteroaryl-(CH₂)—.

As used herein, the term “cycloalkyl,” by itself or as part of anothersubstituent refers to, unless otherwise stated, a cyclic chainhydrocarbon having the number of carbon atoms designated (i.e., C₃-C₆refers to a cyclic group comprising a ring group consisting of three tosix carbon atoms) and includes straight, branched chain or cyclicsubstituent groups. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Other examples are(C₃-C₆)cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

As used herein, the term “halide” refers to a halogen atom bearing anegative charge. The halide anions are fluoride (F⁻), chloride (Cl⁻),bromide (Br⁻), and iodide (I⁻).

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent refers to, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

As used herein, the term “heteroalkenyl” by itself or in combinationwith another term refers to, unless otherwise stated, a stable straightor branched chain monounsaturated or diunsaturated hydrocarbon groupconsisting of the stated number of carbon atoms and one or twoheteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. Up to two heteroatomsmay be placed consecutively. Examples include —CH═CH—O—CH₃,—CH═CH—CH₂—OH, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

As used herein, the term “heteroalkyl” by itself or in combination withanother term refers to, unless otherwise stated, a stable straight orbranched chain alkyl group consisting of the stated number of carbonatoms and one or two heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃.

As used herein, the term “heterocycle” or “heterocyclyl” or“heterocyclic” by itself or as part of another substituent refers to,unless otherwise stated, an unsubstituted or substituted, stable, mono-or multi-cyclic heterocyclic ring system that consists of carbon atomsand at least one heteroatom selected from the group consisting of N, O,and S, and wherein the nitrogen and sulfur heteroatoms may be optionallyoxidized, and the nitrogen atom may be optionally quaternized. Theheterocyclic system may be attached, unless otherwise stated, at anyheteroatom or carbon atom that affords a stable structure. A heterocyclemay be aromatic or non-aromatic in nature. In certain embodiments, theheterocycle is a heteroaryl.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Examples includetetrahydroquinoline and 2,3-dihydrobenzofuryl.

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl(such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl,thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyland 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but notlimited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl,tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl(such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl,phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin,dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but notlimited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl,1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-,5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, butnot limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl,acridinyl, pyrrolizidinyl, and quinolizidinyl.

The aforementioned listing of heterocyclic and heteroaryl moieties isintended to be representative and not limiting.

As used herein, the term “substituted” refers to that an atom or groupof atoms has replaced hydrogen as the substituent attached to anothergroup.

As used herein, the term “substituted”, such as in “substituted alkyl,”“substituted cycloalkyl,” “substituted alkenyl” or “substituted alkynyl”refers to alkyl, cycloalkyl, alkenyl or alkynyl, as defined above,substituted by one, two or three substituents selected from the groupconsisting of halogen, —OH, alkoxy, tetrahydro-2-H-pyranyl, —NH₂,—N(CH₃)₂, (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, —C(═O)OH, trifluoromethyl, —C(═O)O(C₁-C₄)alkyl, —C(═O)NH₂,—C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —C(═NH)NH₂, and—NO₂, preferably containing one or two substituents selected fromhalogen, —OH, alkoxy, —NH₂, trifluoromethyl, —N(CH₃)₂, and —C(═O)OH,more preferably selected from halogen, alkoxy and —OH. Examples ofsubstituted alkyls include, but are not limited to, 2,2-difluoropropyl,2-carboxycyclopentyl and 3-chloropropyl.

For aryl, aryl-(C₁-C₃)alkyl and heterocyclic groups, the term“substituted” as applied to the rings of these groups refers to anylevel of substitution, namely mono-, di-, tri-, tetra-, orpenta-substitution, where such substitution is permitted. Thesubstituents are independently selected, and substitution may be at anychemically accessible position. In certain embodiments, the substituentsvary in number between one and four. In another embodiment, thesubstituents vary in number between one and three. In yet anotherembodiment, the substituents vary in number between one and two. In yetanother embodiment, the substituents are independently selected from thegroup consisting of C₁₋₆ alkyl, —OH, C₁₋₆ alkoxy, halo, amino, acetamidoand nitro. As used herein, where a substituent is an alkyl or alkoxygroup, the carbon chain may be branched, straight or cyclic.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible sub-ranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual and partialnumbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6.This applies regardless of the breadth of the range.

Compounds

The invention provides protective groups that form cyclic complexes withbenzoxaboroles, thus protecting the B—OH functionality. It should benoted that the present disclosure is exemplified with benzoxaboroles andtheir protected forms, but is equally applicable to oxaboroles and theirprotected forms. As used herein, the term “(benz)oxaborole” refers tobenzoxaborole and/or oxaborole. In certain non-limiting embodiments, thedouble bond in the oxaborole ring is saturated.

In one aspect, the invention provides a compound of formula (I) or (I′),or a salt, solvate, enantiomer, diastereoisomer or tautomer thereof:

wherein;

each occurrence of R¹ is independently selected from the groupconsisting of H, OH, halide, amine, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —C(═NH)NH₂,phosphoric acid, phosphonate, sulfonamide, nitro, cyano, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈ heteroalkyl, optionally substituted C₃-C₈heterocycloalkyl, optionally substituted C₁₋₆ perhaloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, and optionally substituted benzyl;

each occurrence of R² is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl, andoptionally substituted C₁₋₆ perhaloalkyl;

each occurrence of R³ is independently selected from the groupconsisting of H, OH, halide, amine, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₁-C₈ heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl,optionally substituted C₁₋₆ perhaloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,optionally substituted benzyl, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, and—C(═NH)NH₂; and

each occurrence of R⁴ is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl,and optionally substituted C₃-C₈ heterocycloalkyl.

In certain embodiments, each occurrence of R¹ is independently selectedfrom the group consisting of OMe, C₁₋₆ alkoxy, NO₂, CH₂OH, CH₂I, CHO,CN, F, Cl, Br, I, CF₃, CH₂Cl, CH₂Br, C₁₋₆ carboxylate, C₁₋₆ thioether

wherein each occurrence of R^(x) is independently selected from thegroup consisting of H and optionally substituted C₁₋₆ alkyl.

In certain embodiments, each occurrence of R¹ is independently selectedfrom the group consisting of H, C₁₋₆ alkoxy, NO₂, CH₂OH, CH₂I, CHO, CN,F,

In certain embodiments, each occurrence of R¹ is independently selectedfrom the group consisting of H, halide, amine, sulfonamide, nitro,cyano, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₃-C₈ heterocycloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted aryloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, andoptionally substituted benzyl.

In certain embodiments, each occurrence of R³ is independently selectedfrom the group consisting of H, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkyl cyano, optionally substituted C₁₋₆nitroalkyl, optionally substituted C₁₋₆ aminoalkyl,

In certain embodiments, each occurrence of R³ is independently selectedfrom the group consisting of H and optionally substituted C₁-C₆ alkyl.

In certain embodiments, R³ is

wherein both nitrogens on the piperazine are bound to independentlyselected compounds of formula (I) or (I′), thereby linking two compoundsof formula (I) or (I′) through the R₃ substituent.

In certain embodiments, each occurrence of R⁴ is independently selectedfrom the group consisting of H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈heteroalkyl, and optionally substituted C₃-C₈ heterocycloalkyl.

In certain embodiments, the compound of formula (I) is a compound offormula (Ia) or (Ia′):

In certain embodiments, each occurrence of R³ is independently selectedfrom the group consisting of H and optionally substituted methyl.

In certain embodiments, the compound of formula (Ia) is a compoundselected from the group consisting of:

In another aspect, the invention provides a compound of formula (II) or(II′), or a salt, solvate, enantiomer, diastereoisomer or tautomerthereof:

wherein;

each occurrence of R¹ is independently selected from the groupconsisting of H, OH, halide, amine, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —C(═NH)NH₂,phosphoric acid, phosphonate, sulfonamide, nitro, cyano, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈ heteroalkyl, optionally substituted C₃-C₈heterocycloalkyl, optionally substituted C₁₋₆ perhaloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, and optionally substituted benzyl;

R² is selected from the group consisting of H, halo, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈ heteroalkyl, optionally substituted C₃-C₈heterocycloalkyl, and optionally substituted C₁₋₆ perhaloalkyl;

each occurrence of R³ is independently selected from the groupconsisting of H, OH, halide, amine, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₁-C₈ heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl,optionally substituted C₁₋₆ perhaloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,optionally substituted benzyl, carboxylic acid, C(═O)O(C₁-C₄)alkyl,—C(═O)NH₂, —C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, and—C(═NH)NH₂;

R⁴ is selected from the group consisting of H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₁-C₈ heteroalkyl, and optionally substituted C₃-C₈heterocycloalkyl; and

each occurrence of R⁵ is independently selected from the groupconsisting of H and optionally substituted C₁₋₆ alkyl, halide, nitro andnitrile.

In certain embodiments, R¹ is selected from the group consisting of OMe,C₁₋₆ alkoxy, NO₂, CH₂OH, CH₂I, CHO, CN, F, Cl, Br, I, CF₃, CH₂Cl, CH₂Br,C₁₋₆ carboxylate, C₁₋₆ thioether

wherein each occurrence of R^(x) is independently selected from thegroup consisting of H and optionally substituted C₁₋₆ alkyl.

In certain embodiments, each occurrence of R³ is independently selectedfrom the group consisting of H, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkyl cyano, optionally substituted C₁₋₆nitroalkyl, optionally substituted C₁₋₆ aminoalkyl,

In certain embodiments, R³ is

wherein both nitrogens on the piperazine are bound to independentlyselected compounds of formula (II) or (II′), thereby linking twocompounds of formula (II) or (II′) through the R³ substituent.In certain embodiments, the compound of formula (II) or (II′) is acompound of formula (IIa) or (IIa′):

wherein R² is selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, and optionally substituted C₃-C₈ cycloalkyl.

In certain embodiments, the compound of formula (IIa) is a compoundselected from the group consisting of:

wherein R² is selected from the group consisting of H, optionallysubstituted C₁₋₆ alkyl, and optionally substituted C₃-C₈ cycloalkyl.

In certain embodiments, the compounds of formula (I)-(I′) and formula(II)-(II′) are resistant to oxidation. In other embodiments, thecompounds of formula (I)-(I′) and formula (II)-(II′) are stable inaqueous solution. In yet other embodiments, the compounds of formula(I)-(I′) and formula (II)-(II′) are not degraded through columnchromatography wherein the chromatography medium is silica gel.

In certain embodiments, the compounds of formula (I)-(I′) and formula(II)-(II′) can be contacted with an acidic solution and degrade to formthe respective benzoxaborole or oxaborole.

Methods

The invention further provides methods of protecting boronic acidgroups. In certain embodiments, the method comprises reacting theboronic acid containing compound with a compound of formula (III) orformula (IV):

wherein

each occurrence of R² is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, halide, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl, andoptionally substituted C₁₋₆ perhaloalkyl;

each occurrence of R⁴ is independently selected from the groupconsisting of H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl,and optionally substituted C₃-C₈ heterocycloalkyl; and

each occurrence of R⁵ is independently selected from the groupconsisting of H, halide, nitro, nitrile and optionally substituted C₁₋₆alkyl.

In certain embodiments, the boronic acid containing compound is a(benz)oxaborole. In other embodiments, the boronic acid containingcompound is a (benz)oxaborole of formula:

wherein R¹ and R³ are as defined elsewhere herein. In yet otherembodiments, the benzoxaborole compound is a compound selected from thegroup consisting of:

In certain embodiments, the method comprises reacting the boronic acidcontaining compound with a compound of formula (IIIa) or formula (IVa):

In certain embodiments, the invention provides a method of making acompound of formula (Ia), the method comprising contacting a compound offormula (IIIa) with a (benz)oxaborole of formula:

wherein R¹ and R³ are as defined elsewhere herein.

In certain embodiments, the invention provides a method of making acompound of formula (IIa), the method comprising contacting a compoundof formula (IVa) with a (benz)oxaborole of formula:

wherein R¹ and R³ are as defined elsewhere herein.

In certain embodiments, the invention provides methods of deprotectingboronic acid containing compounds, the method comprising contacting acompound of formula (I), formula (I′), formula (Ia), formula (II),formula (II′), or formula (IIa) with an acidic solution to yield a(benz)oxaborole of formula:

wherein R¹ and R³ are as defined elsewhere herein.

The methods and compounds described herein include the use of N-oxides(if appropriate), crystalline forms (also known as polymorphs),solvates, amorphous phases, and/or pharmaceutically acceptable salts ofcompounds having the structure of any compound of the invention, as wellas metabolites and active metabolites of these compounds having the sametype of activity. Solvates include water, ether (e.g., tetrahydrofuran,methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetatesand the like. In other embodiments, the compounds described herein existin unsolvated form.

In certain other embodiments, the compounds of the invention exist astautomers. All tautomers are included within the scope of the compoundsrecited herein.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H. ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. Isotopically-labeled compounds are prepared byany suitable method or by processes using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

In certain other embodiments, the compounds described herein are labeledby other means, including, but not limited to, the use of chromophoresor fluorescent moieties, bioluminescent labels, or chemiluminescentlabels.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and in the art. General methods for the preparation ofcompound as described herein are modified by the use of appropriatereagents and conditions, for the introduction of the various moietiesfound in the formula as provided herein.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that, wherever values and ranges are providedherein, the description in range format is merely for convenience andbrevity and should not be construed as an inflexible limitation on thescope of the invention. Accordingly, all values and ranges encompassedby these values and ranges are meant to be encompassed within the scopeof the present invention. Moreover, all values that fall within theseranges, as well as the upper or lower limits of a range of values, arealso contemplated by the present application. The description of a rangeshould be considered to have specifically disclosed all the possiblesub-ranges as well as individual numerical values within that range and,when appropriate, partial integers of the numerical values withinranges. For example, description of a range such as from 1 to 6 shouldbe considered to have specifically disclosed sub-ranges such as from 1to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6,and so on, as well as individual numbers within that range, for example,1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadthof the range.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Materials & Methods:

Protection reactions were performed under an ambient atmosphere unlessotherwise specified. Moisture and air sensitive reactions were performedunder an argon atmosphere in flame- or oven-dried glassware.3-(N,N-dimethylamino)-1-propanol (1) was purchased from FisherScientific and used without further purification. All other commerciallyavailable reagents were purchased from Sigma-Aldrich, Acros Organics,Oakwood Chemicals, or Fisher Scientific and used without furtherpurification. Dry tetrahydrofuran (THF) and dichloromethane (DCM) wereobtained from a Pure Solv MD-5 Solvent Purification System.Dichloroethane (DCE) was dried over activated 4 Å molecular sieves(Sigma-Aldrich) for 3 days prior to use. All other solvents wereobtained from Sigma-Aldrich or Fisher Scientific and used withoutfurther purification. Concentration refers to solvent removal on arotary evaporator. NMR spectra data were obtained on a Bucker Avance 400MHz NMR spectrometer. Chemical shifts are reported in parts per million(ppm) against tetramethylsilane (TMS) standard or residual solventsignal (CDCl₃). ¹¹B Spectra are reported in ppm using BF₃*OEt₂ as anexternal standard. ¹³C resonances next to boron are typically notobserved due to quadrupolar relaxation. Mass spectra were obtained on aThermo-Fisher Exactive Orbitrap Mass Spectrometer using Matrix-AssistantInlet Ionization (MAII) as an ionization source (3-nitrobenzonitrilematrix).² Thin layer chromatography was performed on Sorbtech Silica XGAluminum-backed TLC plates. TLC plates were visualized under a UV lamp(short and long wave). Flash column chromatography was performed withSorbtech silica (Porosity 60 Å, Particle size 40-63 μm, 230×400 mesh).Columns that were run with triethyl amine (TEA) were neutralized with2-3 column volumes of stated mobile phase before loading sample. Theprotected complexes are very hygroscopic. Solids that have absorbedmoisture from the air may be dissolved in a minimum volume of acetone,precipitated with hexane, and concentrated to afford a dry solid.

Synthesis of Protecting Groups

N-methylsalicylidenimine (2). Salicylaldehyde (6 mL, 56 mmol) wasdissolved in absolute EtOH (150 mL) in a round-bottom flask. To themixture was added a solution of MeNH₂ (33 wt % in EtOH, 14 mL, 112 mmol)and the reaction immediately became a bright yellow color. The yellowmixture was stirred at room temperature for 8 hours and solvent wasremoved to afford a yellow oil 2 (7.6 g, Quant.) that was used withoutfurther purification. ¹H NMR (CDCl₃, 400 MHz) δ 3.48 (s, 3H), 6.86 (t,1H), 6.94 (d, 1H), 7.24 (d, 1H), 7.29 (t, 1H), 8.34 (s, 1H), 13.4 (br s,1H).

2-[1-(methylimino)ethyl]phenol (3). 2′-hydroxyacetophenone (5 mL, 41.5mmol) was added to a round-bottom flask and dissolved in absolute EtOH(120 mL). A solution of MeNH₂ (33 wt % in EtOH, 16 mL, 128 mmol) wasadded and the mixture was heated to 50° C. for 5 hrs. The reaction wascooled to room temperature and stirred overnight. The solvent wasremoved to afford a yellow solid 3 (6.2 g, Quant.), which was usedwithout further purification. ¹H NMR (CDCl₃, 400 MHz) δ 2.34 (s, 3H),3.34 (s, 3H), 6.75 (t, 1H), 6.92 (d, 1H), 7.29 (t, 1H), 7.49 (d, 1H).

Synthesis of Benzoxaboroles

3-cyanobenzoxaborole (4b)

4-methyl-3-bromobenzonitrile (S1). To a round bottom flask equipped witha magnetic stir bar, 16.8 grams (0.143 mole) of p-tolunitrile and 80 mLof aqueous sulfuric acid (1:1, v/v sulfuric acid:water) were added. Theflask was wrapped in aluminum foil and the reaction was allowed to runin dark to avoid radical reaction. After the mixture was stirred for 10minutes, 25.6 grams of N-bromosuccinimide (0.143 mole) was added to theflask slowly over 20 minutes. The mixture was stirred at roomtemperature for 3 days. Product was extracted from the reaction mixtureby three separate portions of ether. The combined ether solution waswashed by brine and dried over anhydrous sodium sulfate. Solvent wasremoved to afford crude product as a white solid. The product wasisolated via silicon gel chromatography (using 40:1 hexane/ethyl acetatesolution as eluent). ¹H NMR (CDCl₃): δ 2.44 (s, 3H), 7.30 (d, J=7.8 Hz,1H), 7.47 (dd, J=8.0, 1.5 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H).

3-bromo-4-hydroxmethylbenzonitrile (S2). An argon flushed round-bottomflask was charged with 51 (9.9 g, 51 mmol), N-bromosuccinimide (13.6 g,76.5 mmol), benzoyl peroxide (61 mg, 0.25 mmol), and CCl₄ (250 mL). Themixture was brought to reflux for 6 hours and then filtered uponcompletion with CCl₄ (2×20 mL). The resulting crude oil was suspended indioxane:water (1:1, 300 mL) and sodium carbonate (5 g) and brought toreflux overnight. The material was extracted against EtOAc (3×75 mL) andconcentrated to a solid 4, which was used in the next reaction withoutfurther purification. ¹H NMR (CDCl₃, 400 MHz) δ 4.80 (s, 2H), 7.66 (q,2H), 7.82 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 64.29, 112.66, 117.27,121.88, 128.40, 131.25, 135.45, 145.18.

3-bromo-4-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl] benzonitrile (S3). Toa round-bottom flask containing crude S2 was added dry DCM (120 mL) andstirred. Then, p-toluenesulfonic acid (1.30 g, 6.8 mmol, 13 mol % fromS1) was added quickly followed by DHP (6.5 mL, 76.6 mmol, 1.5 eq fromS1) at room temperature. The resulting solution was stirred overnight.The reaction was quenched with saturated NaHCO₃ (150 mL) and transferredto a separatory funnel. The aqueous layer was extracted with DCM (3×150mL) and combined organics were washing with water and brine. Theorganics were concentrated and will be subjected to flash chromatography(SiO₂, Gradient 20:1 Hexanes:EtOAc-4:1 Hexanes:EtOAc) to afford S3 (4.94g, 32.5% from S1) as a clear liquid. ¹H NMR (CDCl₃, 400 MHz) δ 1.5-1.8(m, 7H), 3.56 (m, 1H), 3.86 (s, 1H), 4.57 (d, 1H, J=15), 4.78 (m, 1H),4.85 (d, 1H, J=15), 7.61 (d, 1H, J=8), 7.67 (d, 1H, J=8).

3-cyanobenzoxaborole (4b). To a flame-dried round-bottom flask was addedS3 (4.94 g, 16.6 mmol) and THF (60 mL). The flask was cooled to −78° C.and BuLi solution (2.5 M in hexanes, 7.3 mL, 18.3 mmol) was addeddropwise via syringe over 15 minutes. After the addition, the mixturewas stirred at −78° C. for 30 minutes. B(OiPr)₃ (4.0 mL, 17.3 mmol) wasadded via syringe at −78° C. and the reaction was warmed to roomtemperature to stir for 3 hours. Then, the reaction was cooled to 0° C.,quenched with water (20 mL), and diluted with EtOAc and extracted (3×75mL). The combined organics were dried over Na₂SO₄ and concentrated to acrude residue. Without purification, the residue was dissolved in MeOH(75 mL) and p-TSA (1.5 g, 8.3 mmol) was added. The mixture was stirredovernight at room temperature and then concentrated to an oil. Theresidue was quickly dissolved in EtOAc and extracted with 1M hydroxide(2×30 mL). The aqueous layer was acidified with c. HCl and backextracted with EtOAc (3×75 mL), combined organics were dried, andconcentrated to produce a yellow solid S3 (873 mg, 33%), which wasanalytically pure and did not require further purification. ¹H NMR(DMSO-d₆, 400 MHz) δ 5.07 (s, 2H), 7.64 (d, 1H, J=8), 7.92 (d, 2H, J=8),9.52 (s, 1H). ¹¹B NMR (DMSO-d₆, 128 MHz) δ 32.38.

3-hydroxymethylbenzoxaborole (4c)

2-bromo-terephthalic acid (S4). To a 2.5 L round-bottom flask were added2-bromo-p-xylene (55.5 g, 0.3 mol), 1.2 L water, and KMnO4 (94.8 g, 0.6mol). The mixture was refluxed slowly until the color faded. Then asecond KMnO4 (47.4 g, 0.3 mol) was added. After the color faded, a thirdKMnO4 (47.4 g, 0.3 mol) was added. The reaction was stopped when thesolution was colorless again. The mixture was filtered to remove theinsoluble salt. The collected filtrates was acidified to pH 3-4 by HClwhen large amount of white solid precipitated from the solution. Thecrude product was collected by filtration and washed with water, thendried under vacuum to yield 30.6 g of 2-bromoterephthalic acid (yield41.7%). 1H NMR (400 MHz, DMSO-d₆, δ, ppm): 8.15 (d, J=1.4 Hz, ArH orthoto Br, 1H), 7.99 (dd, J=8.0, 1.5 Hz, ArH meta to Br, 1H), 7.84 (d, J=8.0Hz, ArH para to Br, 1H).

2-bromo-1,4-bis(hydroxymethyl)benzene (S5). A flame-dried round-bottomflask was charged with S4 (5.5 g, 22.4 mmol) and fitted with apressure-equalizing addition funnel. The solid was dissolved in THF (100mL) and cooled to 0° C. To the addition funnel was added BH₃*THF (1M inTHF, 50 mL, 50 mmol) dropwise over 45 minutes. This mixture was stirredat 0° C. for 1 hour, warmed to room temperature, and stirred for 3hours. The reaction was quenched slowly with the addition of methanol(50 mL) and the mixture was concentrated. The solid residue wasdissolved in EtOAc and water (40 mL) and transferred to a separatoryfunnel. The aqueous layer was extracted with EtOAc (3×75 mL), combinedorganics were washed with brine, dried over Na₂SO₄ and concentrated toafford a white solid S5 (3.89 g, 80%) which needed no furtherpurification. ¹H NMR (DMSO-d₆, 400 MHz) δ 4.48 (t, 4H), 5.28 (t, 1H),5.39 (t, 1H), 7.29 (d, 1H, J=7.8), 7.49 (m, 2H)¹³C NMR (DMSO-d₆, 100MHz) δ 61.8, 62.4, 120.8, 125.5, 127.9, 129.7, 139.1, 143.3.

Alcohol protection with Dihydropyran (S6). To a round-bottom flaskcontaining S5 (3.89 g, 17.9 mmol) was added dry DCM (100 mL) and thesolid was suspended by stirring. Then, p-toluenesulfonic acid (390 mg,2.05 mmol) was added quickly followed by DHP (4.2 mL, 49.5 mmol) at roomtemperature. The mixture became homogeneous upon vigorous stirring andthe resulting solution was stirred overnight. The reaction was quenchedwith saturated NaHCO₃ (30 mL) and transferred to a separatory funnel.The aqueous layer was extracted with DCM (3×75 mL) and combined organicswere washing with water and brine. The organics were concentrated andthe residue was subject to flash chromatography (SiO₂, 9:1Hexanes:EtOAc) to afford a clear oil 5 (5.22 g, 75%). ¹H NMR (CDCl₃, 400MHz) 1.62-1.87 (m, 12H), 3.54 (m, 2H), 3.88 (m, 2H), 4.47 and 4.58 (2×d,1H each), 4.69-4.82 (overlapping d and t, 4H), 7.28 (d, 2H, J=11.7),7.46 (d, 2H, J=7.8), 7.56 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 19.2,19.3, 25.42, 25.44, 30.4, 30.5, 62.14, 62.17, 97.7, 98.3, 126.6, 129.0,131.6, 136.9, 139.3.

Synthesis of 5-hydroxymethylbenzoxaborole (4c). To a flame-driedround-bottom flask was added S6 (5.2 g, 13.5 mmol) and THF (50 mL). Theflask was cooled to −78° C. and BuLi solution (2.5 M in hexanes, 5.6 mL,14 mmol) was added dropwise via syringe over 30 minutes. After theaddition, the mixture was stirred at −78° C. for 30 minutes. B(OiPr)₃(3.2 mL, 15.1 mmol) was added via syringe at −78° C. and the reactionwas warmed to room temperature to stir for 3 hours. Then, the reactionwas cooled to 0° C., quenched with saturated NH₄Cl (40 mL), and dilutedwith water/EtOAc. The aqueous layer was extracted with EtOAc (3×50 mL)and combined organics were washed with brine, dried over Na₂SO₄, andconcentrated. The crude residue was dissolved in MeOH (100 mL) and p-TSA(1.39 g, 7.30 mmol) was added. The mixture was stirred for 5 hours atroom temperature and then concentrated to an oil. The residue wasquickly dissolved in EtOAc and extracted (3×50 mL) against water (˜40mL). Combined organics were washed with brine and dried over Na₂SO₄.Solvent removal produced an off-white solid, which was suspended inhexanes, filtered, and washed with diethyl ether (3×20 mL) to produce awhite solid 4c (1.7 g, 77%). The compound was analytically pure and didnot require further purification. ¹H NMR (MeOD, 400 MHz) δ 4.52 (s, 2H),4.95 (s, 2H), 7.34 (d, 1H, J=7.8), 7.40 (d, 1H, J=7.8), 7.38 (s, 1H).¹¹B NMR (MeOD, 128 MHz) δ 32.01.

3-nitrobenzoxaborole (4d). 1 g (7.4 mmol, 1 equiv.) of commerciallyavailable benzoxaborole was added with stirring to 6.4 mL of fumingnitric acid (18.3 equiv.) cooled at −45/−40° C. The addition was doneportion-wise and was complete in about 5 min. The mixture was stirredand maintained at −45 to −30° C., and the progress of the reaction wasmonitored by TLC (ethyl acetate:petroleum ether=7:3). After 20 min. themixture was poured into water and ice and kept at 0-10° C. for 2 hours.The obtained white precipitate was then filtered in vacuo, washed withwater and lyophilized to afford the compound as a white solid. M.p.178-180° C.; Rf: 0.32 (ethyl acetate:petroleum ether=7:3); ¹H NMR (400MHz, DMSO-d₆): δ 9.59 b (s, 1H, OH), 8.58 (ss, 1H, ArH), 8.33 (d, J=1.7Hz, 1H, ArH), 8.33 (dd, J 1=8.3 Hz, J 2=2.2 Hz, 1H, ArH), 7.69 (d, J=8.5Hz, 1H, ArH), 5.12 (s, 2H, CH2). 13C NMR (101 MHz, DMSO-d₆) δ 160.6,147.2, 140.7, 125.6, 123.1, 70.1 (s, CH2). MS: ESI: m/z 178.0 [M]t

Protection of Benzoxaboroles

Protection of benzoxaborole with N,N-dimethylaminopropanol (5a). To anopen round-bottom flask was added 4a (200 mg, 1.49 mmol), anhydrousNa₂SO₄ (1.68 g, 11.8 mmol), and ether:acetone (1:1 mixture, 6 mL). Themixture was stirred vigorously and 1 (177 μL, 1.50 mmol) was added atRT. Stirring continued for 5.5 hours at RT, diluted with EtOAc (˜5 mL),and filtered. The filter cake was washed with EtOAc (3×8 mL) and thefiltrate was concentrated to afford 5a (230 mg, 98%) as a hygroscopicwhite solid. The compound was analytically pure and did not requirefurther purification. ¹H NMR (CDCl₃, 400 MHz) δ 1.92 (br t, 2H). 2.44(s, 6H), 3.15 (br s, 2H), 4.05 (br t, 2H), 5.04 (s, 2H), 7.16 (br m,3H), 7.52 (br d, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 24.19, 45.42, 58.32,60.10, 71.91, 120.60, 125.94, 127.45, 129.65, 150.06. ¹¹B NMR (CDCl₃,128 MHz) δ 10.35. HRMS (MAII) calc. for C₁₂H₁₈BNO₂ [M+H]⁺220, 1503.found 220.1514.

Protection of 3-cyanobenzoxaborole with N,N-dimethylaminopropanol (5b).To an open round-bottom flask was added 4b (161 mg, 1.01 mmol),anhydrous Na₂SO₄ (1.20 g, 8.47 mmol), and ether:acetone (1:1 mixture, 10mL). The mixture was stirred vigorously and 1 (120 μL, 1.02 mmol) wasadded at RT. Stirring continued for 5.5 hours at RT, diluted with EtOAc(˜5 mL), and filtered. The filter cake was washed with EtOAc (3×8 mL)and the filtrate was concentrated to afford 5 (223 mg, 90%) as ahygroscopic yellowish solid. The compound was analytically pure and didnot require further purification. ¹H NMR (CDCl₃, 400 MHz) δ 1.93 (br s,2H), 2.16 (br s, OH), 3.15 (br s, 2H), 3.99 (br s, 2H), 5.04 (s, 2H),7.25 (d, 1H, J=12), 7.52 (d, 1H, J=12), 7.79 (s, 1H). ¹³C NMR (CDCl₃,100 MHz) δ 23.98, 45.46, 58.44, 60.06, 71.81, 109.83, 120.17, 121.52,131.46, 133.65, 155.43. ¹¹B NMR (CDCl₃, 128 MHz) δ 9.82. HRMS (MAII)calc. for C₁₃H₁₇BN₂O₂ [M+H]⁺ 245.1456. found 245.1447.

Protection of 3-hydroxymethylbenzoxaborole withN,N-dimethylaminopropanol (5c). To an open round-bottom flask was added4c (200 mg, 1.22 mmol), anhydrous Na₂SO₄ (1.3 g, 9.15 mmol), andether:acetone (1:1 mixture, 10 mL). The mixture was stirred vigorouslyand 1 (144 μL, 1.22 mmol) was added at RT. Stirring continued for 5.5hours at RT, diluted with EtOAc (˜5 mL), and filtered. The filter cakewas washed with EtOAc (3×8 mL) and the filtrate was concentrated toafford 5c (301 mg, 98%) as a hygroscopic white solid. The compound wasanalytically pure and did not require further purification. ¹H NMR(CDCl₃, 400 MHz) δ 1.88 (br t, 2H), 2.41 (s, 3.09 (br s, 2H), 3.99 (br1, 2H), 4.66 (br s, 2H), 5.00 (s, 2H), 7.13 (d, J=7.6), 7.25 (br s, 1H),7.51 (br s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 24.36, 45.44, 58.37, 60.24,65.75, 71.67, 120.69, 127.08, 128.60, 138.66, 149.83. ¹¹B NMR (CDCl₃,128 MHz) δ 10.28. HRMS (MAII) calc, for C₁₃H₂₀BNO₃ [M+H]⁺ 250.1609.found 250.1611.

Protection of benzoxaborole with Salicimine (9a). A round-bottom flaskwas charged with a stirbar, 4a (153 mg, 1.14 mmol), and a solution of 2(196 mg, 1.45 mmol) in toluene (8 mL). The flask was fitted with aDean-Stark trap and the suspension was brought to reflux for 5 hours.The reaction was then cooled to RT, concentrated, and the resultingresidue was subjected to flash chromatography (SiO₂, EtOAc w/ 0.5% TEA)to afford 9a (235 mg, 82% yield) as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 3.18 (s, 3H), 5.04 (d, 1H, J=13.8), 5.20 (d, 1H, J=13.8), 6.88(t, 1H), 7.02 (d, 1H, J=8.4), 7.21 (m, 2H), 7.30 (m, 2H), 7.37 (d, 1H,J=7), 7.49 (t, 1H), 8.16 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 42.89,72.33, 115.56, 118.82, 119.83, 120.63, 126.50, 127.77, 128.52, 130.86,137.47, 148.97, 160.20, 162.48. ¹¹B NMR (CDCl₃, 128 MHz) δ 8.95. HRMS(MAII) calc. for C₁₅H₁₄BNO₂ [M+H]⁺ 252.1190. found 252.1181.

Protection of 3-cyanobenzoxaborole with Salicimine (9b). A round-bottomflask was charged with a stirbar, 4b (165 mg, 1.04 mmol), and a solutionof 2 (196 mg, 1.45 mmol) in toluene (15 mL). The flask was fitted with aDean-Stark trap and the mixture was brought to reflux for 5 hours. Thereaction was then cooled to RT, concentrated to a minimum amount oftoluene (1-2 mL), and precipitated with hexane. After cooling to promotefurther precipitation, the solid was filtered and washed with coldhexane (3×5 mL) to afford 9b (221 mg, 77% yield) as a yellowish solid.The compound was analytically pure and did not require furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 3.18 (s, 3H), 5.06 (d, 1H,J=15.2), 5.22 (d, 1H, J=15.2), 6.93 (t, 1H), 7.01 (d, 1H, J=8.4), 7.31(d, 1H, J=7.8), 7.35 (d, 1H J=7.6), 7.56 (t, 1H), 8.22 (s, 1H). ¹³C NMR(CDCl₃, 100 MHz) δ 42.75, 72.15, 110.33, 115.34, 119.39, 119.68, 120.09,121.54, 131.09, 131.67, 132.85, 138.07, 154.13, 159.76, 163.19. ¹¹B NMR(CDCl₃, 128 MHz) δ 8.47. HRMS (MAII) calc. for C₁₆H₁₃BN₂O₂ [M+H]⁺277.1143. found 277.1135.

Protection of 3-hydroxymethylbenzoxaborole with Salicimine (9c). Around-bottom flask was charged with a stirbar, 4c (415 mg, 2.53 mmol),and a solution of 2 (400 mg, 2.96 mmol) in toluene (10 mL). The flaskwas fitted with a Dean-Stark trap and the suspension was brought toreflux for 5 hours. The reaction was then cooled to room temperature andhexane (30 mL) was added. The resulting precipitate was filtered, washedwith cold hexanes (3×10 mL), and dried in vacuo to afford 9c (711 mg,87% yield) as a white, fluffy solid. The compound was analytically pureand did not require further purification. ¹H NMR (CDCl₃, 400 MHz) δ 3.17(s, 3H), 4.64 (s, 2H), 5.03 (d, 1H, J=13.8), 5.18 (d, 1H, J=13.9), 7.00(d, 1H, J=8.4), 7.20 (d, 1H, 7.6), 7.29 (t, 2H), 7.36 (s, 1H) 7.49 (t,1H), 8.15 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 42.83, 65.84, 72.13,115.48, 118.90, 119.74, 120.79, 127.17, 127.29, 130.93, 137.56, 139.10,148.63, 160.07, 162.58. ¹¹B NMR (CDCl₃, 128 MHz) δ 8.86. HRMS (MAII)calc. for C₁₆H₁₆BNO₃ [M+H]⁺ 282.1296. found 282.1288.

Protection of 3-nitrobenzoxaborole with Salicimine (9d). A round-bottomflask was charged with a stirbar, 4d (207 mg, 1.18 mmol), and a solutionof 2 (233 mg, 1.73 mmol) in toluene (15 mL). The flask was fitted with aDean-Stark trap and the solution was brought to reflux overnight. Thereaction was then cooled to room temperature, concentrated to an oil,and precipitated with hexanes. The mixture was concentrated again andthe solid was subject to column chromatography (SiO₂, 4:1 EtOAc:Hexaneswith 1% triethylamine) to afford 9d (298 mg, 85% yield) as a yellowishsolid. ¹H NMR (CDCl₃, 400 MHz) δ 3.19 (s, 3H), 5.09 (d, J=15.5), 5.24(d, 1H, J=15.5), 6.93 (t, 1H), 7.00 (d, 1H, J=8.4), 7.35 (t, 2H), 7.54(t, 1H), 8.15 (d, 1H, J=8.2), 8.19 (s, 1H), 8.23 (s, 1H). ¹³C NMR(CDCl₃, 100 MHz) δ 42.70, 71.92, 119.42, 119.64, 121.45, 123.57, 123.87,131.15, 138.16, 147.65, 156.21, 159.74, 163.35. ¹¹B NMR (CDCl₃, 128 MHz)δ 8.48. HRMS (MAII) calc. for C₁₅H₁₃BN₂O₄ [M+H]⁺ 297.1041. found297.1058.

Protection of Benzoxaborole with 2-[1-(methylimino)ethyl]phenol (10a). Around-bottom flask was charged with a stirbar, 4a (910 mg, 6.81 mmol), 3(1.22 g, 8.17 mmol) and toluene (10 mL). The flask was fitted with aDean-Stark trap and the suspension was brought to reflux for 5 hours.The reaction was then cooled to room temperature, concentrated to aminimum amount of toluene (1-2 mL), and hexane (30 mL) was added. Theresulting precipitate was filtered, washed with cold hexanes (3×10 mL),and dried in vacuo to afford 10a (1.0 g, 55% yield) as an off-whitesolid. The compound was analytically pure and did not require furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 2.57 (s, 3H), 3.09 (s, 3H), 5.04(d, 1H, J=13.8), 5.20 (d, 1H, J=13.8), 6.88 (t, 1H), 7.03 (d, 1H,J=8.3), 7.19 (m, 2H), 7.30 (m, 2H), 7.45 (t, 1H), 7.58 (d, 1H, J=8). ¹³CNMR (CDCl₃, 100 MHz) δ 16.30, 37.05, 72.05, 117.38, 118.59, 120.67,126.41, 127.60, 127.93, 128.39, 136.28, 148.89, 159.38, 170.08. ¹¹B NMR(CDCl₃, 128 MHz) δ 8.74. HRMS (MAII) calc. for C₁₆H₁₆BNO₂ [M+H]⁺266.1347. found 266.1371.

Protection of 3-cyanobenzoxaborole with 2-[1-(methylimino)ethyl]phenol(10b). A round-bottom flask was charged with a stirbar, 4b (150 mg,0.940 mmol), 3 (196 mg, 1.32 mmol), and toluene (10 mL). The flask wasfitted with a Dean-Stark trap and the suspension was brought to refluxfor 5 hours. The reaction was then cooled to room temperature,concentrated to a minimum amount of toluene (1-2 mL), and hexane (30 mL)was added. The resulting precipitate was filtered, washed with coldhexanes (3×˜10 mL), and dried in vacuo to afford 10b (100 mg, 36% yield)as a yellowish solid. The compound was analytically pure and did notrequire further purification. ¹H NMR (CDCl₃, 400 MHz) δ 2.60 (s, 3H),3.07 (s, 3H), 5.07 (d, 1H, J=15.1), 5.21 (d, 1H, J=15.1), 6.93 (t, 1H),7.01 (d, 1H, J=8.3), 7.29 (d, 1H, J=7.8), 7.49 (t, 1H), 7.54 (d, 1H,J=7.8), 7.58 (s, 1H), 7.60 (d, 1H, J=8.1). ¹³C NMR (CDCl₃, 100 MHz) δ16.48, 36.95, 71.89, 110.20, 117.15, 119.18, 120.18, 120.51, 121.55,128.14, 131.48, 132.75, 136.84, 154.07, 158.87, 171.09. ¹¹B NMR (CDCl₃,128 MHz) δ 8.35. HRMS (MAII) calc. for C₁₇H₁₅BN₂O₂ [M+H]⁺ 291.1299.found 291.1325.

Protection of 3-hydroxymethylbenzoxaborole with2-[1-(methylimino)ethyl]phenol (10c). A round-bottom flask was chargedwith a stirbar, 4c (403 mg, 2.45 mmol), 3 (435 mg, 2.91 mmol), andtoluene (10 mL). The flask was fitted with a Dean-Stark trap and thesuspension was brought to reflux for 5 hours. The reaction was thencooled to room temperature and hexane (30 mL) was added. The resultingprecipitate was filtered, washed with cold hexanes (3×10 mL), and driedin vacuo to afford 10c (723 mg, 87% yield) as a white, fluffy solid. Thecompound was analytically pure and did not require further purification.¹H NMR (CDCl₃, 400 MHz) δ 2.57 (s, 3H), 3.08 (s, 3H), 4.63 (s, 2H), 5.03(d, 1H, J=13.9), 5.18 (d, 1H, J=13.9), 6.88 (t, 1H), 7.02 (d, 1H,J=8.3), 7.21 (d, 1H, J=7.6), 7.31 (d, 2H), 7.46 (t, 1H), 7.58 (d, 1H,J=8.1). ¹³C NMR (CDCl₃, 100 MHz) δ 16.32, 37.08, 65.94, 71.87, 117.21,118.68, 120.61, 120.85, 127.05, 127.24, 127.99, 136.38, 138.95, 148.65,159.23, 170.20. ¹¹B NMR (CDCl₃, 128 MHz) δ 8.72. HRMS (MAII) calc. forC₁₇H₁₈BNO₃ [M+H]⁺ 296.1453. found 296.1446.

Protection of 3-nitrobenzoxaborole with 2-[1-(methylimino)ethyl]phenol(10d). A round-bottom flask was charged with a stirbar, 4d (184 mg, 1.23mmol), 3 (203 mg, 1.12 mmol), and toluene (25 mL). The flask was fittedwith a Dean-Stark trap and the mixture was brought to reflux for 5hours. The reaction was then cooled to room temperature, concentrated toa minimum amount of toluene (1-2 mL), and hexane (30 mL) was added. Theresulting precipitate was filtered, washed with cold hexanes (3×˜10 mL),and dried in vacuo to afford 10d (288 mg, 83% yield) as a yellow solid.The compound was analytically pure and did not require furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 2.62 (s, 3H), 3.09 (s, 3H), 5.10(d, 1H, J=15.5), 5.24 (d, 1H, J=15.5), 6.93 (t, 1H), 7.01 (d, 1H,J=8.4), 7.33 (d, 1H, J=8.2), 7.49 (t, 1H), 7.62 (d, 1H, J=8), 8.14 (2s,2H). ¹³C NMR (CDCl₃, 100 MHz) δ 16.45, 36.95, 71.65, 119.17, 120.47,121.40, 123.39, 123.77, 128.16, 136.92, 156.14, 158.79. ¹¹B NMR (CDCl₃,128 MHz) δ 8.25. HRMS (MAII) calc. for C₁₆H₁₅BN₂O₄ [M+H]⁺ 311.1198.found 311.1190.

Functionalization of Benzoxaboroles

DIBAL-H reduction of nitrile (6). To a round-bottom flask containing 5b(212 mg, 0.865 mmol) was added DCM (7 mL) and the solution was cooled to−78° C. DIBAL-H (1M in Hexane, 1.3 mL, 1.3 mmol) was added dropwise viasyringe over 15 minutes. After addition, the reaction was stirred for 30minutes at −78° C. and then warmed to RT over 8 hours. The reaction wasquenched with EtOAc (12 mL) and 1M HCl (8 mL), which also promoteddeprotection. The mixture was transferred to a separatory funnel withadditional EtOAc (˜15 mL) and water (5 mL). The mixture was extractedand the aqueous layer was treated with additional EtOAc (2×15 mL),combined organics were washed with brine, and dried over Na₂SO₄.Concentration afforded an off-white solid 6 (111 mg, 79%) which wasanalytically pure and did not require further purification. ¹H NMR(DMSO-d₆, 400 MHz) δ 5.08 (s, 2H), 7.63 (d, 1H, J=7.8), 8.00 (d, 1H,J=7.8), 8.27 (s, 1H), 9.45 (s, 1H, B—OH), 10.06 (s, 1H). ¹³C NMR(DMSO-d₆, 100 MHz) δ 70.58, 122.80, 132.01, 132.81, 135.86, 160.77,193.63. ¹¹B NMR (DMSO-d₆, 128 MHz) δ 31.65. HRMS (MAII) calc. forC₈H₇BO₃ [M+H]⁺ 163.0561. found 163.0568.

Oxidation of alcohol with MnO₂ (6). In a round-bottom flask, 5c (211 mg,0.850 mmol) was dissolved in dry DCM (6 mL) and MnO₂ (1.2 g, 13.8 mmol)was added at RT. The mixture was stirred for 32 hours at RT, filteredover celite, and the filter cake was washed with EtOAc (3×15 mL). Thefiltrate was transferred to a separatory funnel and washed with 1M HCl(˜20 mL) to promote deprotection. The organic layer was dried overNa₂SO₄ and concentrated to an off-white solid 6 (99 mg, 72%) which didnot require further purification. Characterization data matches theabove reaction.

Synthesis of 3-iodomethylbenzoxaborole (7). To a dry round-bottom flaskwith a stir bar was added 5c (245 mg, 0.983 mmol) and NaI (460 mg, 3.06mmol). Chlorotrimethylsilane (375 μL, 2.95 mmol) was added dropwise over5 min at 0° C., allowed to stir at 0° C. for 5 more min, and warmed tort for 3 hr. The mixture was concentrated, dissolved in ether (25 mL)and 1M HCl (˜10 mL), and transferred to a separatory funnel. The aqueouslayer was extracted once more with ether (25 mL) and combined organicswere washed once with sat'd NaHSO₃ and once with sat'd brine. Theorganic layer was dried over Na₂SO₄, filtered, concentrated, and driedin vacuo to afford a dry, white solid 7 (181 mg, 72%) which did notrequire further purification. ¹H NMR (CDCl₃, 400 MHz) δ 4.52 (s, 2H),5.06 (s, 2H), 7.29 (d, 1H, J=7.9), 7.51 (d, 1H, J=7.8), 7.75 (s, 1H).¹³C NMR (CDCl₃, 100 MHz) δ 5.47, 71.21, 121.66, 130.50, 131.77, 138.51,153.53, ¹¹B NMR (CDCl₃, 128 MHz) δ 32.24. HRMS (MAII) calc. for C₈H₈BO₂[M−I]⁺ 147.0612. found 147.0623.

Mitsunobu reaction (8). To a round-bottom flask containing 5c (165 mg,0.662 mmol) was added PS—PPh₃ (2.32 mmol/g loading, 730 mg, 1.69 mmol)and phthalimide (150 mg, 1.02 mmol). THF (6 mL) was added, cooled to 0°C., and DIAD (195 μL, 1.02 mmol) was added dropwise over 15 min. Thereaction was stirred for an additional 15 min at 0° C. and warmed to rtfor 24 h. The mixture was filtered, resin washed with EtOAc (3×10 mL),and the filtrate was washed with 1M HCl (5 mL) in a separatory funnel topromote deprotection. The organic phase was absorbed onto silica andsubjected to flash chromatography (SiO₂, 20:1 DCM:Acetone→1:1DCM:Acetone) to afford 8 (124 mg, 64%) as a white solid. ¹H NMR (CDCl₃,400 MHz) δ 4.91 (s, 2H), 5.06 (s, 2H), 7.30 (d, 1H, J=7.8), 7.46 (t,1H), 7.57 (d, 1H, J=7.8), 7.70 (m, 2H), 7.80 (s, 1H), 7.84 (2H). ¹³C NMR(CDCl₃, 100 MHz) δ 41.50, 71.06, 121.42, 123.39, 128.44, 130.47, 131.59,132.07, 134.03, 135.39, 153.55, 168.06. ¹¹B NMR (CDCl₃, 128 MHz) δ32.76, HRMS (CI) calc. for C₁₆H₁₂BNO₄ [M−1]⁻ 292.0895. found 292.0881.

Dess-Martin Oxidation of Salicylimine-protected aldehyde (11a). Around-bottom flask containing a stirbar was charged with Dess-Martinperiodinane (550 mg, 1.29 mmol), anhydrous NaHCO₃ (259 mg, 3.08 mmol),and 9c (305 mg, 1.08 mmol). Dry DCM (10 mL) and dry THF (4 mL) wereadded to the round-bottom flask at room temperature and the mixture wasstirred at room temperature for 4 hours. The reaction was quenched withsaturated Na₂S₂O₄ (6 mL), stirred for 5 minutes, and transferred to aseparatory funnel. The layers were separated and the aqueous layer wasextracted with DCM (2×15 mL). Combined organics were washed with brine,dried over Na₂SO₄, and concentrated. The residue was subject to columnchromatography (SiO₂, EtOAc with 1.5% triethylamine) to afford 11a (247mg, 82%) as a hydroscopic yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 3.19(s, 3H), 5.09 (d, 1H, J=15.3), 5.25 (d, 1H, J=15.3), 6.92 (t, 1H), 7.01(d, 1H, J=8.4), 7.36 (t, 1H), 7.52 (t, 1H), 7.81 (d, 1H, J=7.7), 7.89(s, 1H), 8.21 (d, 1H), 9.98 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 42.75,72.16, 115.36, 119.21, 119.69, 121.35, 130.10, 130.49, 131.05, 135.56,137.93, 156.33, 159.90, 163.05. ¹¹B NMR (CDCl₃, 128 MHz) δ 8.66. HRMS(MAII) calc. for C₁₆H₁₄BNO₃ [M+H]⁺ 280.1140. found 280.1133.

Collins Reagent Oxidation of Salicylimine-protected alcohol (11a). To adry round-bottom flask containing a stir bar and dry DCM (5 mL) wasadded pyridine (340 μL, 4.20 mmol). The flask was flushed with argon,cooled to 0° C., and CrO₃ (219 mg, 2.19 mmol) was added in one portion.The mixture was allowed to stir for 45 min at 0° C. after which 9c (100mg, 0.37 mmol) was added in one portion. The mixture was stirred at 0°C. for 1 hr, filtered over silica, and washed acetone (5×5 mL). Thefiltrate was concentrated and the resulting brown solid was subjected tocolumn chromatography (SiO₂, EtOAc with 1.5% triethylamine) to afford11a (60 mg, 58%) as a hydroscopic yellow solid. Characterization exactlymatches the previous procedure for 11a.

Dess-Martin Oxidation of -protected alcohol (11b). Synthesized by thesame procedure as 11a from 10c (300 mg, 1.01 mmol), Dess-Martinperiodinane (519 mg, 1.21 mmol), anhydrous NaHCO₃ (254 mg, 3.03 mmol) indry DCM (10 mL) and dry THF (4 mL) to produce 11b (148 mg, 50%), whichwas purified by column chromatography (SiO₂, EtOAc with 1.5%triethylamine). ¹H NMR (CDCl₃, 400 MHz) δ 2.59 (s, 3H), 3.07 (s, 3H),5.09 (d, 1H, J=15.3), 5.25 (d, 1H, J=15.3), 6.89 (t, 1H), 7.01 (d, 1H,J=8.3), 7.36 (d, J=7.8, 1H), 7.46 (t, 1H), 7.60 (d, J=8.1, 1H), 7.79 (s,J=7.7, 1H), 7.83 (s, 1H), 9.96 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ16.39, 36.97, 71.90, 117.08, 118.96, 120.52, 121.36, 128.10, 129.99,130.31, 135.51, 136.69, 156.33, 159.01, 170.82, 193.09. ¹¹B NMR (CDCl₃,128 MHz) δ 8.55. HRMS (MAII) calc. for C₁₇H₁₆BNO₃ [M+H]⁺ 294.1296. found294.1274.

Reductive amination (12). In a round-bottom flask, 11a (103 mg, 0.369mmol) was dissolved in dry dichloroethane (4 mL). 4-chloroaniline (50mg, 0.392 mmol) and AcOH (20 μL, 0.349 mmol) were added and the mixturewas stirred at room temperature for 8 hours. After this time, sodiumtriacetoxyborohydride (130 mg, 0.613 mmol) was added and stirred at roomtemperature for 16 hrs. The mixture was concentrated to a residue thatwas absorbed onto silica and subjected to flash chromatography (SiO₂,20:1 DCM:Acetone with 1% triethylamine) to afford 12 (105 mg, 73%) as ayellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 3.17 (s, 3M), 4.24 (s, 2H), 5.03(d, 1H, J=13.8), 5.20 (d, 1H, J=13.8), 6.55 (d, 2H, J=8.6), 6.89 (t,1H), 7.02 (d, 1H, J=8.4), 7.08 (d, 2H, J=8.6), 7.20 (d, 1H, J=7.6), 7.30(t, 2H), 7.35 (s, 1H), 7.50 (t, 1H), 8.17 (s, 1H). ¹³C NMR (CDCl₃, 100MHz) δ 42.92, 48.74, 72.14, 113.85, 115.44, 118.95, 119.78, 120.92,121.78, 127.57, 127.83, 128.96, 130.92, 136.79, 137.58, 146.89, 148.49,160.06, 162.59. ¹¹B NMR (CDCl₃, 128 MHz) δ 8.83. HRMS (MAII) calc. forC₂₂H₂₀BClN₂O₂ [M+H]⁺ 391.1379. found 391.1385, calc. for C₁₆H₁₆BNO₂[M-N(4-ClPh)]⁺ 264.1190. found 264.1193.

Acetylation of amine (13). To a dry round-bottom flask was added 12 (47mg, 0.120 mmol) and DCM (3 mL). Triethylamine (35 μL, 0.251 mmol) andacetic anhydride (40 μL, 0.420 mmol) were added via microsyringe underargon and stirred at RT for 5 hours. After this time, the mixture wasconcentrated and the crude residue was subjected to flash chromatography(EtOAc w/ 2% TEA→3:1 EtOAc:Acetone) to afford 13 (26 mg, 51%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz) δ 1.84 (s, 3H), 3.09 (s, 3H), 6.63 (d,1H, J=14), 4.99 (d, 1H, J=13.9), 5.05 (d, 1H, J=14.1), 5.14 (d, 1H,J=13.9), 6.87 (m, 3H), 6.99 (d, 1H, J=8.4), 7.09 (m, 3H), 7.24 (d, 2H,J=8.5), 7.29 (d, 1H, J=7), 7.48 (1, 1H), 8.14 (s, 1H). ¹³C NMR (CDCl₃,100 MHz) δ 22.82, 42.76, 52.73, 72.11, 115.50, 118.90, 119.70, 120.70,128.65, 129.28, 129.56, 129.84, 130.91, 133.56, 134.96, 137.53, 141.30.¹¹B NMR (CDCl₃, 128 MHz) δ 8.81. HRMS (MAII) calc. for C₂₄H₂₂BN₂O₃[M+H]⁺ 433.1485. found 433.1493.

Oxidation of aldehyde with KMnO₄ (14). To a round-bottom flaskcontaining a solution of 11a (108 mg, 0.386 mmol) in acetone (4 mL) wasadded solid KMnO₄ (198 mg, 1.25 mmol) in one portion at rt. The mixturewas stirred for 3 h and then filtered over a pad of celite. The filtercake was washed with acetone (2×10 mL) and the purple filtrate wasconcentrated. To the residue was added EtOAc (15 mL) and sat'd NaHSO₃ (5mL, corrected to ˜pH 3 with HCl). The mixture was transferred to areparatory funnel, extracted, and the aqueous phase was extracted withanother portion of EtOAc (10 mL). The combined organics were dried overNa₂SO₄ and concentrated to afford 14 (21 mg, 17%). Workup can also bemodified by diluting the crude reaction mixture with EtOAc (˜15 ML) andextracting against sat'd NaHSO₃ (˜10 mL) and 1M HCl (˜15 ML). Theaqueous phase was extracted again with EtOAc (˜15 mL), combined organicsdried, and concentrated. The resulting residue was resuspended inEtOAc:Acetone (1:1), decanted, and concentrated to afford 14 in 50%yield. White solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 3.09 (s, 3H), 7.02 (d,2H, J=15.3), 7.68 (d, 1H, J=15.3), 7.80 (s, 1H), 8.07 (d, 2H), 9.07 (s,1H), 13.01 (br s, 1H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 42.35, 115.50,116.24, 118.77, 119.35, 120.80, 125.43, 133.04, 133.66, 133.68, 138.69,140.20, 158.30, 168.30, 170.50. ¹¹B NMR (DMSO-d₆, 128 MHz) δ 5.38. HRMS(MAII) calc. for C₁₆H₁₂BNO₅ [M+H]⁺ 294.0932. found 294.0912.

Bromination via Appel Reaction (15). To a dry round-bottom flask wasadded 9c (111 mg, 0.394 mmol), PPh₃ (141 mg, 0.537 mmol), andN-bromosuccinimide (107 mg, 0.601 mmol). DCM (5 mL) was added todissolved at 0° C. and stirred for 1 h. The mixture was warmed to rt for2 h and then concentrated to a solid residue. ¹H NMR showed completeconversion to the benzylic bromide. The residue was subjected to flashchromatography (SiO₂, DCM:ACN 9:1) to afford pure 15 (49 mg, 36%).Hygroscopic white solid. ¹H NMR (CDCl₃, 400 MHz) δ 3.18 (s, 3H), 4.51(s, 2H), 5.03 (d, 1H, J=14.2), 5.17 (d, 1H, J=14.2), 6.89 (t, 1H), 7.01(d, 1H, J=8.4), 7.20 (d, J=7.8), 7.33 (d, 2H, J=7.7), 7.38 (s, 1H), 7.50(t, 1H), 8.19 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 34.83, 42.93, 72.09,115.45, 119.01, 119.76, 121.08, 129.01, 129.30, 130.96, 135.95, 137.65,149.49, 159.99, 162.74. ¹¹B NMR (CDCl₃, 128 MHz) δ 8.75. HRMS (MAII)calc. for C₁₆H₁₅BNO₂ [M−Br+H]⁺ 264.1190. found 264.1179.

Deprotection of Complexes with 2

Deprotection to isolate benzoxaborole (4a). To a round-bottom flaskcontaining a solution of 9a (150 mg, 0.60 mmol) in THF (2 mL) was added1M HCl (4 mL) at RT. The mixture was stirred for 2 hours at RT, afterwhich the mixture was diluted with EtOAc (˜10 mL). The mixture wastransferred to a separatory funnel containing water (˜5 mL) andextracted. The aqueous layer was extracted further with EtOAc (2×10 mL)and the combined organics were washed with saturated sodium bisulfite(2×10 mL) and brine. After drying over Na₂SO₄, the organic phase wasconcentrated to afford 4a (80 mg, Quant.) as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 5.12 (s, 2H), 5.18 (s, 1H), 0.35 (t, 1H), 739 (t 1H),7.74 (d, 1H). ¹¹B NMR (128 MHz, CDCl₃) δ 32.60.

Deprotection to isolate 3-cyanobenzoxaborole (4b). To a round-bottomflask containing a solution of 9b (150 mg, 0.60 mmol) in THF (5 mL) wasadded 1M HCl (2.6 mL) at RT. The mixture was stirred for 2 hours at RT,after which the mixture was diluted with EtOAc (˜10 mL). The mixture wastransferred to a separatory funnel containing water (˜5 mL) andextracted. The aqueous layer was extracted further with EtOAc (2×10 mL)and the combined organics were washed with saturated sodium bisulfite(2×10 mL) and brine. After drying over Na₂SO₄, the organic phase wasconcentrated to afford 4b (55 mg, 88%) as an off-white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 4.24 (s, 1), 6.80 (d, 1H), 706 (d, 1H), 7.10 (s,1H), 8.66 (s, 1H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 70.63, 110.43, 119.69,123.38, 134.40, 135.03, 159.14. ¹¹B NMR (DMSO-d₆, 128 MHz) δ 31.50.

Example 1: Benzoxaborole Protection Using3-(N,N-dimethylamino)-1-propanol

Oxidation of primary alcohol (4c) with pyridinium chlorochromate (PCC)in the presence of the benz-oxaborole functionality has proven difficultin the past. 4c has extremely poor solubility and attempts at oxidationresulted in complex mixtures and very low yields of the desired aldehydeproduct. Solubility was increased by making the methyl or ethyl estersof the benzoxaborole, but complex mixtures were still obtained underoxidative conditions. In order to address the solubility andchemoselectivity issues, novel benzoxaborole protecting groups weresought out. Such protecting groups should a) be inexpensive and readilysynthesized, b) be able to withstand mild oxidation conditions, and c)improve the solubility of benzoxaboroles, especially ones containinghydrogen bonding substituents.

Molecules that form 6-membered ring complexes via an ester linkage anddative coordination of a nitrogen were explored. Without wishing to belimited to any particular theory, nitrogen coordination could mask thebenzoxaborole boron's p-orbital, which would help decrease sidereactivity and possibly improve solubility of compounds withcoordinating substituents. To this end, three benzoxaborole protectinggroups: 3-(N,N-dimethylamino)-1-propanol 1, N-methyl salicylidenimine 2,and 2-[1-(methylimino)ethyl]phenol 3 were explored.

Compounds containing both an alcohol and amine, which would form astable, 6-membered ring with the oxaborole, were explored. Amino alcohol1, which is commercially available and inexpensive, readily coordinatedwith benzoxaboroles in good yields upon stirring at room temperature inether:acetone to form complexes 5a-c. During isolation of the product,it was found that the complexes underwent rapid deprotection whenexposed to an aqueous environment. Because of the lability of thesecomplexes, complexes 5a-c may be best suited for one-step sequenceswhere the benzoxaborole is protected in situ without furtherpurification, transformed, and readily deprotected and isolated duringthe reaction workup. It was observed that the organic solubility ofthese complexes significantly increased compared to the respectivebenzoxaborole counterparts. Compound 4b was subjected todiisobutylaluminum hydride (DIBAL-H) followed by aqueous workup, whichresulted in clean conversion to aldehyde 6 as the only product. Whilethere is detectable product formation when unprotected, DIBAL-H normallycauses partial decomposition of the benzoxaborole and leads to a complexreaction mixture which requires chromatographic purification.

Benzylic alcohol oxidation with manganese dioxide proceeded in goodyield as another method of producing 6 after deprotection via extractiveworkup. An iodisation reaction and a Mitsubobu reaction were alsoconducted to produce the benzyl iodide 7 and substitution product 8,respectively, after deprotection via workup. No reaction was observedwhen 4c was not protected due to its lack of solubility in the reactionmedium. These examples provided evidence that solubility affects thereactivity of these compounds. Based on the promising results with 1,protecting groups that would be stable to column chromatography andsuitable across multiple synthetic steps were sought out.

Example 2: Benzoxaborole Protection Using N-methylsalicylidenimine and2-[1-(methylimino)ethyl]phenol

Using the backbone of 1 as a scaffold, a phenolic alcohol wasincorporated in order to provide both an increase in complex rigidityand stability. After unsuccessfully evaluating several phenolico-benzylamine compounds, compounds 2 and 3 were found to have thedesired properties.

These protecting groups are readily synthesized from cheap, commerciallyavailable salicylaldehyde or 2′-hydroxyacetophenone in excellent yieldsvia condensation with methylamine as described in the literature. Tosynthesize protected benzoxaboroles 9a-d and 10a-d, compounds 2 and 3,respectively, were refluxed with the corresponding benzoxaborole intoluene under Dean-Stark conditions. All of these protected complexeswere stable to mild aqueous conditions, but aqueous acid and strongaqueous base resulted in deprotection. The complexes were found to bestable to aqueous extraction and could be purified by columnchromatography.

Additional reactions in the presence of protecting groups 2 and 3 werethen explored. Of particular interest were methods of functionalizationof alcohols that were previously limited by poor solubility and chemicalincompatibility. As discussed in Example 1, attempts to oxidize 6without protection were either unsuccessful or resulted in complexproduct mixtures. Protection of 6 with 2 and 3 allowed for thesuccessful oxidization of the primary alcohols to aldehydes 9c and 10cwith Dess-Martin perioidinane (DMP) in higher yields than reported inthe literature and with no observed side reactivity. Oxidation with PCCwas attempted, but the acidic nature of the reagent, even when absorbedonto neutral alumina or buffered with sodium acetate, lead todeprotection. This observation was confirmed upon successfully oxidizing9c with Collins reagent in 58% yield, proving that the complex canwithstand some Cr (VI) reagents.

The stability of the protected species was then explored under reducingconditions. The aldehyde products were subjected to reductive aminationconditions in the presence of 4-chloroaniline and sodiumtriacetoxyborohydride to produce amine 12 in 73% yield. Reactivity wasfound to be similar when using 2 and 3. Attempts were made tofunctionalize 12 by subjecting it to an Appel reaction to make reactivebenzylic electrophiles. The reaction proceeded smoothly and the productremained intact, but separation of the triphenylphosphine oxidebyproduct proved challenging.

Optimal deprotection conditions were explored for removing 2 from theprotected complexes. It was observed that mild aqueous acidic conditionslead to deprotection of these complexes. 1M HCl in THF solvent was foundto smoothly deprotect 9a and 9b at room temperature in two-three hoursand did not require column chromatography to re-isolate the freebenzoxaborole. Avoiding the need for column chromatography isadvantageous because chromatography of unprotected benzoxaborolesusually results in low recovered yields.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety. While this invention has been disclosed with referenceto specific embodiments, it is apparent that other embodiments andvariations of this invention may be devised by others skilled in the artwithout departing from the true spirit and scope of the invention. Theappended claims are intended to be construed to include all suchembodiments and equivalent variations.

1. A compound of formula (II) or (II′), or a salt, solvate, enantiomer,diastereoisomer, or tautomer thereof:

wherein: each occurrence of R¹ is independently selected from the groupconsisting of H, OH, halogen, amine, carboxylic acid,C(═O)O(C₁-C₄)alkyl, C(═O)NH₂, C(═O)NH(C₁-C₄)alkyl,C(═O)N((C₁-C₄)alkyl)₂, C(═NH)NH₂, phosphoric acid, phosphonate,sulfonamide, nitro, cyano, optionally substituted C₁-C₆ alkyl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₁-C₈ heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl,optionally substituted C₁-C₆ perhaloalkyl, optionally substituted C₁-C₆alkoxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,and optionally substituted benzyl, R² is selected from the groupconsisting of H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl, andoptionally substituted C₁-C₆ perhaloalkyl; each occurrence of R³ isindependently selected from the group consisting of H, OH, halogen,amine, optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl, optionallysubstituted C₃-C₈ heterocycloalkyl, optionally substituted C₁-C₆perhaloalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted aryl, optionally substituted aryloxy, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, optionally substitutedbenzyl, carboxylic acid, C(═O)O(C₁-C₄)alkyl, C(═O)NH₂,C(═O)NH(C₁-C₄)alkyl, C(═O)N((C₁-C₄)alkyl)₂, SO₂NH₂, and C(═NH)NH₂; eachoccurrence of R⁴ is independently selected from the group consisting ofH, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₁-C₈ heteroalkyl, and optionallysubstituted C₃-C₈ heterocycloalkyl; and each occurrence of R⁵ isindependently selected from the group consisting of H, optionallysubstituted C₁-C₆ alkyl, halogen, nitro, and nitrile.
 2. The compound ofclaim 1, wherein each occurrence of R¹ is independently selected fromthe group consisting of OMe, C₁-C₆ alkoxy, NO₂, CH₂OH, CH₂I, CHO, CN, F,Cl, Br, I, CF₃, CH₂Cl, CH₂Br, C₁-C₆ carboxylate, C₁-C₆ thioether,

wherein each occurrence of R^(x) is independently selected from thegroup consisting of H and optionally substituted C₁-C₆ alkyl.
 3. Thecompound of claim 1, wherein each occurrence of R³ is independentlyselected from the group consisting of H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ cyanoalkyl, optionally substitutedC₁-C₆ nitroalkyl, optionally substituted C₁-C₆ aminoalkyl,


4. The compound of claim 1, which is a compound of formula (IIa) or(IIa′):

wherein R² is selected from the group consisting of H and methyl.
 5. Thecompound of claim 4, wherein the compound of formula (IIa) is a compoundselected from the group consisting of:

wherein R² is selected from the group consisting of H, optionallysubstituted C₁-C₆ alkyl, and optionally substituted C₃-C₈ cycloalkyl. 6.A method of protecting a boronic acid group, the method comprisingreacting a boronic acid containing compound with a compound of formula(III) or formula (IV):

wherein: each occurrence of R² is independently selected from the groupconsisting of H, optionally substituted C₁-C₆ alkyl, halogen, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl, andoptionally substituted C₁-C₆ perhaloalkyl; each occurrence of R⁴ isindependently selected from the group consisting of H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈ heteroalkyl, and optionally substitutedC₃-C₈ heterocycloalkyl; and each occurrence of R⁵ is independentlyselected from the group consisting of H, halogen, nitro, nitrile, andoptionally substituted C₁-C₆ alkyl.
 7. The method of claim 6, whereinthe boronic acid containing compound is a (benz)oxaborole or oxaborole.8. The method of claim 7, wherein the (benz)oxaborole or oxaborole is acompound of formula:

wherein: each occurrence of R¹ is independently selected from the groupconsisting of H, OH, halogen, amine, carboxylic acid,C(═O)O(C₁-C₄)alkyl, C(═O)NH₂, C(═O)NH(C₁-C₄)alkyl,C(═O)N((C₁-C₄)alkyl)₂, C(═NH)NH₂, phosphoric acid, phosphonate,sulfonamide, nitro, cyano, optionally substituted C₁-C₆ alkyl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₁-C₈ heteroalkyl, optionally substituted C₃-C₈ heterocycloalkyl,optionally substituted C₁-C₆ perhaloalkyl, optionally substituted C₁-C₆alkoxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,and optionally substituted benzyl; and each occurrence of R³ isindependently selected from the group consisting of H, OH, halogen,amine, optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl, optionallysubstituted C₃-C₈ heterocycloalkyl, optionally substituted C₁-C₆perhaloalkyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted aryl, optionally substituted aryloxy, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, optionally substitutedbenzyl, carboxylic acid, C(═O)O(C₁-C₄)alkyl, C(═O)NH₂,C(═O)NH(C₁-C₄)alkyl, C(═O)N((C₁-C₄)alkyl)₂, SO₂NH₂, and C(═NH)NH₂. 9.The method of claim 6, wherein the boronic acid containing compound isselected from the group consisting of:


10. The method of claim 6, comprising reacting the boronic acidcontaining compound with a compound of formula (IIIa) or formula (IVa):


11. A method of deprotecting a boronic acid containing compound, themethod comprising contacting either: (a) a compound of claim 1; or (b) acompound of claim 1, wherein each R⁵ is H and R² is selected from thegroup consisting of H and methyl; with an acidic solution to yield a(benz)oxaborole or oxaborole of formula:


12. A compound of formula (I) or (I′), or a salt, solvate, enantiomer,diastereoisomer or tautomer thereof:

wherein: each occurrence of R¹ is independently selected from the groupconsisting of H, halogen, amine, sulfonamide, nitro, cyano, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₃-C₈ heterocycloalkyl, optionally substitutedC₁-C₆ alkoxy, optionally substituted aryloxy, optionally substitutedheteroaryl, and optionally substituted heteroaryloxy; each occurrence ofR² is independently selected from the group consisting of H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl, optionallysubstituted C₃-C₈ heterocycloalkyl, and optionally substituted C₁-C₆perhaloalkyl; each occurrence of R³ is independently selected from thegroup selected from the group consisting of H and optionally substitutedC₁-C₆ alkyl; each occurrence of R⁴ is independently selected from thegroup consisting of H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ heteroalkyl,and optionally substituted C₃-C₈ heterocycloalkyl.
 13. The compound ofclaim 12, wherein each occurrence of R¹ is independently selected fromthe group consisting of H, NO₂, CH₂OH, CH₂I, CHO, CN, F,


14. The compound of claim 12, which is a compound of formula (Ia) or(Ia′):

wherein: each occurrence of R¹ is independently selected from the groupconsisting of H, halogen, amine, sulfonamide, nitro, cyano, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₃-C₈ heterocycloalkyl, optionally substitutedC₁-C₆ alkoxy, optionally substituted aryloxy, optionally substitutedheteroaryl, and optionally substituted heteroaryloxy; each occurrence ofR³ is independently selected from the group consisting of H andoptionally substituted methyl; each occurrence of R⁴ is independentlyselected from the group consisting of H, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₁-C₈ heteroalkyl, and optionally substituted C₃-C₈ heterocycloalkyl.15. A compound, or a salt, solvate, enantiomer, diastereoisomer ortautomer thereof, selected from the group consisting of: